Radiotherapeutic formulations containing 224RA and a method for their production

ABSTRACT

The invention relates to novel radiotherapeutic formulations containing  224 Ra and methods for their production. The invention discloses, in particular, radiotherapeutic formulations comprising at least one salt of the isotope  224 Ra, which are characterized in that the content of other radionuclides, in particular, the respective content of certain longeval radionuclides does not exceed a specific numerical value in mBq/g. The invention also relates to a method for producing radiotherapeutic formulations of this type, which is characterized by the following steps: after at least one centrifugation of an aqueous suspension of the compound  228 Th(OH) 4  and optionally after the resuspension of the raw sediment obtained in said centrifugation, the precipitated  228 Th(OH) 4  sediment is separated. The supernatant solution of a  224 Ra salt that has been obtained is subsequently subjected to sterile filtration and is then made up to the required dose. Finally, said solution is sterilized and bottled in ampoules in a manner known per se.

SPECIFICATION

This invention relates to novel, ²²⁴Ra-containing, radiotherapeutic formulations and processes for their production.

Ankylosing spondylitis (Bechterew's disease) is a clinical picture which has been known for a long time and which is accompanied by degenerative ossification processes of the spinal column and residual spinal curvature. The use of formulations based on salts of the radioisotope ²²⁴Ra for treatment of this disease is prior art which likewise has been known for decades. Thus Orhan Delikan in the literature citation Health Physics, Vol. 35 (July), pp. 21-24, Pergamon Press Ltd., 1978 describes that the limitation of the content of contaminating radioisotopes, such as for example the especially long-lived, alpha particle-emitting nuclides ²²⁸Th, ²²⁶Ra, ²²⁸Ra or ²²⁷Ac, acquires decisive importance for the success or failure of one such therapy. These contaminants are easily incorporated by the patient into the bone substance and accumulated there as a result of their pronounced structure-chemical isomorphism with the isotope ²²⁴Ra; this works against the actual radiotherapy or is at least associated with considerable side effects which burden the patient. Since production of the therapeutic isotope ²²⁴Ra proceeding from the isotope ²²⁸Th takes place with emission of an alpha particle (⁴He), both prior purification of the parent material ²²⁸Th which has been used and also subsequent separation of the resulting product isotope ²²⁴Ra as thoroughly as possible from the reaction mixture with respect to the desired production of a therapeutic agent which is as effective as possible without undesirable peripheral effects and side effects acquire great importance.

According to the prior art the parent material ²²⁸Th is purified by ion exchange chromatographic separation of the aforementioned disruptive isotopes. Then precipitation of the ²²⁸Th as a poorly soluble hydroxide and washing of the sediment take place. After the daughter isotope ²²⁴Ra is newly formed over the course of roughly 5 to 10 days, then extraction of the ²²⁸Th which is present as the hydroxide in an aqueous solution takes place using a calcium chloride solution; after being repeated several times this leads to a more or less pure aqueous (²²⁴Ra)RaCl₂ solution.

The two above described purification steps are however described as extremely unsatisfactorily by specialists. Thus the aforementioned literature citation from Delikan in the paragraph between pages 22 and 23 remarks that ²²⁸Th extraction is “very critical” since here different boundary conditions and process parameters which are difficult to adjust must be watched at the same time; adherence to them subsequently makes it difficult or impossible to effectively carry out the purification step even for the best trained and equipped individual skilled in the art. On page 23, left column, at the start of the first complete paragraph it is moreover noted that ²²⁴Ra-containing formulations which have been produced using one such process of the prior art generally contain a still measurable residual content of the aforementioned, long-lived radionuclides in spite of all purification steps; this can be attributed to the fact that the salts of these nuclides are not completely insoluble and thus in part even after extraction of the ²²⁸Th remain in the therapeutically used ²²⁴Ra formulation.

Thus, according to the prior art there is a demand for a radiotherapeutic formulation for treatment of ankylosing spondylitis (=Bechterew's disease) which a priori avoids the above described defects of the formulations of the prior art by a degree of purity which is higher than in known formulations, especially by a much lower content of the above described long-lived nuclides ²²⁸Th, ²²⁶Ra, ²²⁸Ra or ²²⁷Ac.

It has unexpectedly been found that this object is achieved by a novel therapeutic formulation which contains the ²²⁴Ra isotope.

This formulation as claimed in the invention comprises at least one salt of the isotope ²²⁴Ra and is characterized in that the content of other radionuclides, especially the content of the radionuclides cited below, does not exceed the indicated numerical value for each:

Maximum Radionuclide: concentration (mBq/g) ²²⁸Ra 60 ²²⁸Th 30 ²¹⁰Pb 30 ²²⁶Ra 30 ²³⁸U 20 ²³¹Pa 60 ²²⁷Ac 10 ²³²U 50.

According to one preferred embodiment the formulation as claimed in the invention is characterized in that the content of other radionuclides, especially the content of the radionuclides which are listed below, does not exceed the indicated numerical value for each:

Maximum Radionuclide: concentration (mBq/g) ²²⁸Ra 26 ²²⁸Th 3.6 ²¹⁰Pb 23 ²²⁶Ra 29 ²³⁸U 19 ²³¹Pa 55 ²²⁷Ac 9.3 ²³²U 20.

According to one especially preferred embodiment the formulation as claimed in the invention is characterized in that the content of other radionuclides, especially the content of the radionuclides which are listed below, does not exceed the indicated numerical value for each:

Maximum Radionuclide: concentration (mBq/g) ²²⁸Ra 22 ²²⁸Th 3.3 ²¹⁰Pb 17 ²²⁶Ra 26 ²³⁸U 15 ²³¹Pa 55 ²²⁷Ac 8.4 ²³²U 5.

According to another preferred embodiment the formulation as claimed in the invention is characterized in that the salt of the radionuclide ²²⁴Ra is radium chloride (²²⁴RaCl₂). Moreover, the formulation as claimed in the invention preferably comprises an isotonic solution, especially preferably of a calcium salt, especially calcium chloride.

The formulation as claimed in the invention is produced using a process which is characterized in that the process steps (a) to (d) which are described below are carried out:

-   (a) At least one-time centrifuging of an aqueous suspension of the     compound ²²⁸Th(OH)₄, optionally after resuspension of the resulting     raw sediment; -   (b) Separation of the ²²⁸Th(OH)₄ sediment which has been     precipitated after step (a); -   (c) Sterile filtration and subsequent bottling of the desired dose     of the supernatant solution of the ²²⁴Ra salt which was obtained     after step (b); -   (d) Sterilization of the bottling obtained after step (c) in the     conventional manner.

One preferred embodiment of the process as claimed in the invention is characterized in that the centrifuging in step (a) is carried out twice and the resulting precipitate is resuspended afterwards using an isotonic aqueous solution, especially preferably of a calcium salt, especially a 1.14% by weight CaCl₂ solution.

Another especially preferred embodiment of the process as claimed in the invention is characterized in that centrifuging is carried out in step (a) with a rotational speed corresponding to a centrifugal acceleration of 2000 g for 10 minutes.

Another preferred embodiment of the process as claimed in the invention is characterized in that the separation in step (b) is carried out by suction and filtration.

Another preferred embodiment of the process as claimed in the invention is characterized in that sterile filtration in step (c) is carried out using a known sterile material, especially preferably using a material based on a fluorine-containing organic service polymer or an optionally modified and/or derivatized polysaccharide.

One especially preferred embodiment of the process as claimed in the invention is characterized in that the sterile filter material is cellulose, cellulose acetate or polytetrafluorethylene, especially preferably cellulose acetate.

One preferred embodiment of the process as claimed in the invention is characterized in that the sterile filter material has a pore size in the range from roughly 0.01 micron to 10 microns, especially preferably in the range from roughly 0.2 micron to 5 microns and especially roughly 0.2 microns.

Another preferred embodiment of the process as claimed in the invention is characterized in that the sterilization step (d) is carried out using a conventional autoclave, especially preferably at a temperature of roughly 121° C. for roughly 20 minutes.

Another preferred embodiment of the process as claimed in the invention is characterized in that the therapeutic salt of the radionuclide ²²⁴Ra is radium chloride (²²⁴RaCl₂).

This invention is described in greater detail in the following text sections using the corresponding representative embodiments.

EMBODIMENTS 1. Production of [²²⁸Th] Thorium Hydroxide

Production of ²²⁸Th

Production of ²²⁸Th takes place proceeding from ²³¹ Pa by the ²³¹P(n y) ²³²Pa reaction. The ²³² Pa which has been formed in this reaction decays first into ²³²U and then into ²²⁸Th. For production, the daughters of protactinium pentoxide were removed from it, the protactinium pentoxide was sealed in quartz vials and irradiated in a reactor. After a decay time of a few weeks ion exchange chromatographic separation of the ²³²U(t_(1/2)=72 years) took place; its was captured as the chloride, dried and stored in order to obtain ²²⁸Th.

This material was dissolved in HNO₃ and passed via an anion exchange column. Under these conditions thorium is bound as [Th(NO₃)₆]²⁻ on the column and the daughters of ²²⁸Th and ²³²U were washed from the column using HNO₃. Then ²²⁸Th was washed from the column with 0.5 m HCl. After determining the concentration, this solution was transferred to glass vessels and dried.

Production of [²²⁸Th] Thorium Hydroxide

1. The [²²⁸Th] thorium chloride is taken up using the carrier solution [²³²Th] thorium nitrate pentahydrate in hydrochloric acid 10%, Ph. Eur.*) in component steps in the primary container and transferred into a 50 ml centrifuge tube.

2. The insoluble thorium hydroxide is precipitated from this solution with ammonia solution (26%). Calcium chloride solution is added to 30 ml and centrifuging is done at 2000 g for 10 minutes. The addition of [²³²Th] thorium nitrate pentahydrate as the carrier in step 1 guarantees the formation of relatively large amounts of precipitate which can be quantitatively separated by centrifuging, and minimizes adsorption effects of ²²⁸Th.

3. The supernatant is carefully suctioned through a glass suction filter. The residue is mixed with calcium chloride solution 1.14% and after stirring with a magnetic stirrer, centrifuged again. This washing step is repeated once more in order to completely remove traces of unsedimentable thorium hydroxide which may be present. During the last suction the entire supernatant is removed as much as possible.

4. The raw sediment which has been obtained in this manner is dried.

5. The dried raw sediment is resuspended in calcium chloride solution 1.14% and stored in a closed centrifuge tube.

2. Production of [²²⁴Ra] Radium Chloride

Production of [²²⁴Ra] radium chloride takes place in 4 stages. Stages 1-3 are carried out in a gastight box with lead shielding and remote control. The inlet air is filtered sterile by a filter of suspended matter of class S. The required articles can be placed in the box via airlocks.

Stage 1 Extraction and Centrifuging

The soluble [²²⁴Ra] radium chloride is desorbed with calcium chloride solution from the insoluble [²²⁸Th] thorium hydroxide and separated by centrifuging.

This step is repeated several times. The supernatants are withdrawn after each centrifuging and then combined into the batch stock solution. The production suspension is resuspended and stored.

Stage 2 Filling of Injection Vials with Doses

To determine the [²²⁴Ra] radium chloride concentration a radioactivity check measurement of an aliquot of the batch stock solution is taken.

Based on the determined activity concentration the injection vials are filled with the batch stock solution and accordingly calcium chloride solution (1.14%) using a dual syringe-dilutor with sterile syringe end filters. If filling is done for several calibration times on the same day, the amount of the batch stock solution to be added is changed according to the decay of the radium-224 (T_(1/2 phys)=3.66 days) and the amount of calcium chloride solution is increased to make 1.1 ml. The vials are then closed and sealed.

Stage 3 Sterilization

The preparation is sterilized at 121° C. for 20 minutes in a laboratory autoclave.

Stage 4 Labelling of the Outer Containers and Packaging

After sterilization, the vials which were already labelled before filling are removed from the production box and packaged. 

1. A radiotherapeutic formulation comprising at least one salt of the isotope ²²⁴Ra, wherein the content of radionuclides listed below does not exceed the indicated numerical value for each: Maximum Radionuclide: concentration (mBq/g) ²²⁸Ra 26 ²²⁸Th   3.6 ²¹⁰Pb 23 ²²⁶Ra 29 ²³⁸U 19 ²³¹Pa 55 ²²⁷Ac   9.3 ²³²U 
 20.


2. The radiotherapeutic formulation of claim 1, wherein the content of radionuclides listed below does not exceed the indicated numerical value for each: Maximum Radionuclide: concentration (mBq/g) ²²⁸Ra 22 ²²⁸Th   3.3 ²¹⁰Pb 17 ²²⁶Ra 26 ²³⁸U 15 ²³¹Pa 55 ²²⁷Ac   8.4 ²³²U  
 5.


3. The radiotherapeutic formulation of claim 1, wherein the salt of the radionuclide ²²⁴Ra is radium chloride (²²⁴RaCl₂).
 4. The radiotherapeutic formulation of claim 1, wherein the formulation comprises an isotonic.
 5. Process for producing a radiotherapeutic formulation comprising at least one salt of the isotope ²²⁴Ra, wherein the process comprises the steps of: (a) Obtaining ²²⁸Th from ²³²U; (b) Binding the ²²⁸Th of step (a) as the anion [²²⁸Th(NO₃)₆]² on an anion exchange column; (c) Washing the bound ²²⁸Th of step (b) from the anion exchange column using a solution of HCl: (d) Precipitating the resulting ²²⁸Th of step (c) as ²²⁸Th(OH)₄; (e) Resuspending the ²²⁸Th(OH)₄ using an aqueous solution comprising 1.14% by weight CaCl₂ and at least one-time centrifuging the resulting aqueous suspension; and (f) Sterile filtration and subsequent bottling of the desired dose of the supernatant solution of the centrifugation step in step (e); wherein the content of ²²⁸Th in the formulation does not exceed 3.6 mBq/g, and wherein the content of ²²⁷Ac in the formulation does not exceed 9.3 mBq/g.
 6. The process of claim 5, wherein centrifuging is carried out in step (e) with a rotational speed corresponding to a centrifugal acceleration of 2000 g for 10 minutes.
 7. The process of claim 5, wherein sterile filtration in step (f) is carried out using a known sterile filter material.
 8. The process of claim 7, wherein the sterile filter material is cellulose, cellulose acetate or polytetrafluorethylene.
 9. The process of claim 7, wherein the sterile filter material has a pore size in the range from roughly 0.01 micron to 10 microns.
 10. The process of claim 5, further comprising the step of sterilization of the bottled dose obtained after step (f) using a conventional autoclave.
 11. The process of claim 5, wherein the therapeutic salt of radionuclide ²²⁴Ra is radium chloride (²²⁴RaCl₂).
 12. A method of treating ankylosing spondylitis (Bechterew's disease) comprising administering the radiotherapeutic formulation of claim 1 to a patient in need of such a treatment.
 13. The radiotherapeutic formulation of claim 2, wherein the salt of the radionuclide ²²⁴Ra is radium chloride (²²⁴RaCl₂).
 14. The radiotherapeutic formulation of claim 2, wherein the formulation comprises an isotonic.
 15. The radiotherapeutic formulation of claim 3, wherein the formulation comprises an isotonic.
 16. The process of claim 7, wherein the sterile filter material is based on a fluorine-containing organic service polymer or an optionally modified and/or derivatized polysaccharide.
 17. The process of claim 8, wherein the sterile filter material is cellulose acetate.
 18. The process of claim 9, wherein the sterile filter material has a pore size in the range from roughly 0.2 micron to 5 microns.
 19. The process of claim 18, wherein the sterile filter material has a pore size of roughly 0.2 microns.
 20. The process of claim 10, wherein the sterilization step (d) is carried out at a temperature of roughly 121° C. for roughly 20 minutes. 